About 70% of all cases of dementia are due to Alzheimer's disease which is associated with the selective damage of brain regions and neural circuits critical for cognition Alzheimer's disease is characterized by neurofibrillary tangles in particular in pyramidal neurons of the hippocampus and numerous amyloid plaques containing mostly a dense core of amyloid deposits and defused halos.
The extracellular neuritic plaques contain large amounts of a pre-dominantly fibrillar peptide termed “amyloid β”, “A-beta”, “Aβ4”, “β-A4” or “Aβ” (see e.g. Selkoe, D. J., Ann. Rev. Cell Biol. 10 (1994) 373-403; Koo, E. H., Proc. Natl. Acad. Sci. USA 96 (1999) 9989-9990; U.S. Pat. No. 4,666,829; or Glenner, G. G., Biochem. Biophysic. Res. Commun. 122 (1984) 1131-1135). This amyloid β peptide is derived from “Alzheimer precursor protein/β-amyloid precursor protein” (APP). APPs are integral membrane glycoproteins (see e.g. Sisodia, S. S., Proc. Natl. Acad. Sci. USA 89 (1992) 6075-6079) and are endoproteolytically cleaved within the Aβ sequence by a plasma membrane protease, α-secretase (see e.g. Sisodia (1992), loc. cit.). Furthermore, further secretase activity, in particular β-secretase and γ-secretase activity, leads to the extracellular release of amyloid-β(Aβ) comprising either 39 amino acids (Aβ39), 40 amino acids (Aβ40), 42 amino acids (Aβ42) or 43 amino acids (Aβ43) (see e.g. Sinha, S., Proc. Natl. Acad. Sci. USA 96 (1999) 11049-11053; Price, D. L., Science 282 (1998) 1079-1083; WO 00/72880; or Hardy, J., Trends in Neuroscience (1997) 154-159).
It is of note that Aβ has several natural occurring forms, whereby the human forms are referred to as the above mentioned Aβ39, Aβ40, Aβ41, Aβ42 and Aβ43. The most prominent form, Aβ42, has the amino acid sequence (starting from the N-terminus): DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA (SEQ ID NO: 13). In Aβ41, Aβ40, Aβ39, the C-terminal A, IA and VIA, respectively, are missing. In the Aβ43-form an additional threonine residue is comprised at the C-terminus of the above depicted sequence.
Standard solid-phase immunoassays with antibodies involve the formation of a complex between an antibody adsorbed/immobilized on a solid phase (capture antibody), the antigen, and an antibody to another epitope of the antigen conjugated with an enzyme or detectable label (tracer antibody). In the assay, a sandwich is formed: solid phase/capture antibody/antigen/tracer antibody. In the reaction catalyzed by the sandwich among other things the activity of the antibody-conjugated enzyme is proportional to the antigen concentration in the incubation medium. The standard sandwich method is also called double antigen bridging immunoassay because capture and tracer antibodies bind to different epitopes of the same antigen. Hoesel, W., et al. (J. Immunol. Methods 294 (2004) 101-110) report an anti-EPO double antigen bridging assay wherein a mixture of immobilized rhEPO coupled to amino groups and to carbohydrate groups was used. Immunoassays such as the double antigen bridging ELISA are common assay types in the investigation of an immunogenic answer of a patient to a drug antibody. Mire-Sluis, A. R., et al. (J. Immunol. Methods 289 (2004) 1-16) summarize the recommendations for the design and optimization of immunoassays using detection of host antibodies against biotechnology products. Anti-drug antibody assays are mentioned, for example, in WO 2005/045058 and WO 90/006515. Anti-idiotypic antibody assays are mentioned, for example, in U.S. Pat. No. 5,219,730; WO 87/002778; EP 0 139 389; and EP 0 170 302. Wadhwa, M., et al. (J. Immunol. Methods 278 (2003) 1-17) report strategies for the detection, measurement and characterization of unwanted antibodies induced by therapeutic biologicals. In US 2007/0093415 amyloid specific peptides and uses thereof are reported. A method for producing anti idiotypic antibodies is reported in EP 1 917 854.